Squamous Cell Carcinoma Standard and Novel Targets.

Squamous Cell Carcinoma Standard and Novel Targets. Mohamed K. Mohamed, MD, PhD Director of Thoracic Oncology Cone Health Cancer Center Greensboro, NC 1

Mohamed Mohamed, MD, PhD Squamous Cell Carcinoma: Standard and Novel Targets Relevant financial relationships in the past twelve months by presenter or spouse/partner. Speakers Bureau : Eli Lilly, BMS, Merck, Astra Zeneca, Genentech, Boehringer-Ingelheim, Guardant 360 The speaker will directly disclosure the use of products for which are not labeled (e.g., off label use) or if the product is still investigational. 13 th Annual New Orleans Summer Cancer Meeting July 20-22, 2018

Review of current and potential future therapies for squamous cell carcinoma (SCC) of the lung. Derman, et al Transl Lung Cancer Res. 2015 Oct; 4(5): 524 532.

First Line Treatment options For Metastatic Squamous Cell Carcinoma of the Lung 4

Phase III Study: Gemcitabine + Cisplatin vs. Pemetrexed + Cisplatin as First-line Therapy Advanced-stage, previously untreated NSCLC patients (N = 1725) Stratified by: ECOG performance score (0 vs. 1) Disease stage (IIIB vs. IV) Brain metastases (yes vs. no) Sex (male vs. female) Pathologic diagnosis (histologic vs. cytologic) Treatment center Cisplatin 75 mg/m 2 on Day 1 + Gemcitabine 1250 mg/m 2 on Days 1 and 8 Six 3-week cycles Cisplatin 75 mg/m 2 on Day 1 + Pemetrexed 500 mg/m 2 on Day 1 Six 3-week cycles Scagliotti GV, et al. J Clin Oncol. 2008;26:3543-3551.

CP vs. CG in Advanced NSCLC: OS by Histology Nonsquamous Squamous Survival Probability 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 CP CG CP vs. CG 0 6 12 18 24 Median Survival 11.8 months 10.4 months Adjusted HR: 0.81 30 Survival Probability 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 CP CG CP vs. CG 0 6 12 18 24 Median Survival 9.4 months 10.8 months Adjusted HR: 1.23 30 Survival Time (Months) in Patients With Nonsquamous Histology Survival Time (Months) in All Patients With Squamous Histology Scagliotti GV, et al. J Clin Oncol. 2008;26:3543-3551.

Albumin-Bound Paclitaxel + Carboplatin vs. Cremophor EL Paclitaxel + Carboplatin in Advanced NSCLC Study Design Chemotherapy-naïve ECOG PS 0-1 Stage IIIB/IV NSCLC (N = 1052) RANDOMIZED 1:1 AB-paclitaxel 100 mg/m 2 days 1, 8, 15 Carboplatin AUC = 6 day 1 Cycles of 21 days No Premedication (n = 521) CrEL paclitaxel 200 mg/m 2 day 1 Carboplatin AUC = 6 day1 Cycles of 21 days Premedication with Dexamethasone + Antihistamines (n = 531) Socinski MA et al. ASCO. 2011 [Abstract 7551]. AB, albumin-bound; CrEL, Cremophor EL; ECOG, Eastern Cooperative

Albumin-Bound Paclitaxel + Carboplatin vs. Cremophor EL Paclitaxel + Carboplatin in Advanced NSCLC Results: ORR, Stratified by Histology a P < 0.001 RR = 1.680 n=228 n=221 P = 0.808 RR = 1.034 n=292 n=310 AB-paclitaxel 100 mg/m 2 + carboplatin AUC = 6 CrEL paclitaxel 200 mg/m 2 + carboplatin AUC = 6 Interaction P-Value for Histology: 0.036 a Not a pre-specified endpoint. * Not a pre-specified endpoint Socinski MA et al. ASCO. 2011 [Abstract 7551].

PFS (A), OS (B) in the ITT population as well as OS (C) in squamous Cell Carcinoma for CnP vs CP

SQUIRE (CP11-0806): Phase III Trial of Necitumumab plus Gemcitabine and Cisplatin in SqCC NSCLC NSCLC Squamous cell ECOG PS 0-2 N=1093 Gem + Cis + Necitumumab Q3weeks (N=545) 1:1 randomization max of 6 cycles Gem + Cis Q3weeks (N=548) Necitumumab to PD Patient selection was not based in EGFR expression Tatcher N, J Clin Oncol 32:5s, 2014 (suppl; abstr 8008)

SQUIRE: Phase III Trial of Necitumumab plus Gem/Cis in SqCC NSCLC: OS SOBREVIDA GLOBAL Median OS (m) Gem-Cis + Necitumumab 11,5 Gem-Cis 9,9 HR 0,84 IC 95% 0,74-0,96 p value 0,012 Tatcher N, J Clin Oncol 32:5s, 2014 (suppl; abstr 8008)

SQUIRE: Phase III Trial of Necitumumab plus Gem/Cis in SqCC NSCLC: Conclusions SQUIRE is the largest phase III trial exploring the first line treatment of squamous cell lung cancer The study reached its primary endpoint (OS: 11.5 vs. 9.9m; p=0.012) However, minimal delta in PFS and no difference in ORR. The combination of Necitumumab, Gemcitabine and Cisplatin had a manageable toxicity profile. New therapeutic alternative for squamous cell lung cancer. Tatcher N, J Clin Oncol 32:5s, 2014 (suppl; abstr 8008)

Black Box warning for Necitumumab Cardiopulmonary arrest or sudden death occurred in 15 (3%) of 538 patients treated with Necitumumab plus gemcitabine and cisplatin as compared to 3 (0.6%) of 541 patients treated with gemcitabine and cisplatin alone in Study 1 Twelve of the 15 patients died within 30 days of the last dose of Necitumumab and had comorbid conditions including history of coronary artery disease (n=3), hypomagnesemia (n=4), chronic obstructive pulmonary disease (n=7), and hypertension (n=5). Eleven of the 12 patients had an unwitnessed death. Hypomagnesemia occurred in 83% of 461/538 patients with available laboratory results treated with Necitumumab as compared to 70% of 457/541 patients with available laboratory results treated with gemcitabine and cisplatin alone in Study 1.

KEYNOTE-024 Study Design (NCT02142738) Presented By Julie Brahmer at 2017 ASCO Annual Meeting

Kaplan-Meier Estimate of OS: Updated Analysis Presented By Julie Brahmer at 2017 ASCO Annual Meeting

Subset Analysis For Squamous Cell Carcinoma in Keynote 024 16

What is New at ASCO 2018 regarding Metastatic Squamous Cell Carcinoma of the Lung?

IMpower131: Primary PFS and Safety Analysis of a Randomized Phase III Study of Atezolizumab + Carboplatin + Paclitaxel or Nab-Paclitaxel vs Carboplatin + Nab-Paclitaxel as 1L Therapy in Advanced Squamous NSCLC Presented By Robert Jotte at 2018 ASCO Annual Meeting

IMpower131: Study Design Presented By Robert Jotte at 2018 ASCO Annual Meeting

IMpower131: Statistical Testing Plan Presented By Robert Jotte at 2018 ASCO Annual Meeting

Baseline Characteristics in the ITT Population Presented By Robert Jotte at 2018 ASCO Annual Meeting

IMpower 131: PFS and OS Atezo + Chemo vs Chemo Alone

INV-Assessed PFS in Clinical Subgroups Presented By Robert Jotte at 2018 ASCO Annual Meeting

INV-Assessed PFS in PD-L1 Subgroups Presented By Robert Jotte at 2018 ASCO Annual Meeting

INV-Assessed PFS in PD-L1 Subgroups (Arm B vs Arm C) Presented By Robert Jotte at 2018 ASCO Annual Meeting

Confirmed Objective Response Rate and Duration of Response Presented By Robert Jotte at 2018 ASCO Annual Meeting

First Interim OS in PD-L1 Subgroups (Arm B vs Arm C) Presented By Robert Jotte at 2018 ASCO Annual Meeting

Subsequent Cancer Therapies Presented By Robert Jotte at 2018 ASCO Annual Meeting

Safety Summary Presented By Robert Jotte at 2018 ASCO Annual Meeting

Immune-Related AEs of Special Interest in 5 Patients Across Arms Presented By Robert Jotte at 2018 ASCO Annual Meeting

Summary Presented By Robert Jotte at 2018 ASCO Annual Meeting

KEYNOTE-407: Phase 3 Study of Carboplatin-Paclitaxel/Nab-Paclitaxel With or Without Pembrolizumab for Metastatic Squamous NSCLC Presented By Luis Paz-Ares at 2018 ASCO Annual Meeting

Pembrolizumab and First-Line Treatment of Metastatic NSCLC Presented By Luis Paz-Ares at 2018 ASCO Annual Meeting

KEYNOTE-407 Study Design (NCT02775435) Presented By Luis Paz-Ares at 2018 ASCO Annual Meeting

Statistical Considerations Presented By Luis Paz-Ares at 2018 ASCO Annual Meeting

Baseline Characteristics at IA2 Presented By Luis Paz-Ares at 2018 ASCO Annual Meeting

Frequency of PD-L1 TPS Categories Presented By Luis Paz-Ares at 2018 ASCO Annual Meeting

Keynote#407 OS and PFS Pembro + Chemotherapy vs. Chemotherapy alone

Overall Survival at IA2 in Key Subgroups Presented By Luis Paz-Ares at 2018 ASCO Annual Meeting

Overall Survival at IA2 by PD-L1 TPS Presented By Luis Paz-Ares at 2018 ASCO Annual Meeting

Progression-Free Survival by PD-L1 TPS (RECIST v1.1, BICR) Presented By Luis Paz-Ares at 2018 ASCO Annual Meeting

Keynote#407 ORR and DOR: Pembro + Chemo vs. Chemo alone

Exposure to Study Treatment at IA2 Presented By Luis Paz-Ares at 2018 ASCO Annual Meeting

Keynote #407 Adverse effects: Pembro + Chemo vs. Chemo Alone

Summary and Conclusions Presented By Luis Paz-Ares at 2018 ASCO Annual Meeting

Pembrolizumab vs Platinum-Based Chemotherapy as First-Line Therapy for Advanced/Metastatic NSCLC With a PD-L1 TPS 1%: Open-Label, Phase 3 KEYNOTE-042 Study Presented By Gilberto Lopes at 2018 ASCO Annual Meeting

KEYNOTE-042 Study Design Presented By Gilberto Lopes at 2018 ASCO Annual Meeting

Frequency and Response Rate for PDL1 TPS >1%

Duration of Response: TPS 1% (RECIST v1.1, BICR) Presented By Gilberto Lopes at 2018 ASCO Annual Meeting

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Summary and Conclusions Presented By Gilberto Lopes at 2018 ASCO Annual Meeting

Comparative Rate of Mutations Across Different Tumor Types Getz G, and Lawrence M, Broad Institute, MIT

Nivolumab + Ipilimumab, Nivolumab + Chemotherapy, and Chemotherapy in Chemo-Naive Patients With Advanced Non-Small Cell Lung Cancer and <1% Tumor PD-L1 Expression: Results From CheckMate 227 Presented By Hossein Borghaei at 2018 ASCO Annual Meeting

CheckMate 227 Part 1 Study Design Presented By Hossein Borghaei at 2018 ASCO Annual Meeting

PFS, ORR and DOR: Nivolumab + Chemotherapy vs Chemotherapy in Patients With <1% Tumor PDL1 Expression

PFS: Nivolumab + Chemotherapy and Nivolumab + Ipilimumab in Patients With TMB 10 mut/mb and <1% Tumor PD-L1 Expression Presented By Hossein Borghaei at 2018 ASCO Annual Meeting

DOR: Nivolumab + Chemotherapy and Nivolumab + Ipilimumab in Patients With TMB 10 mut/mb and <1% Tumor PD-L1 Expression Presented By Hossein Borghaei at 2018 ASCO Annual Meeting

PFS Subgroup Analyses in Patients With <1% Tumor PD-L1 Expression Presented By Hossein Borghaei at 2018 ASCO Annual Meeting

PFS: Nivolumab vs. Chemotherapy vs. Nivolumab + Ipilumumab by TMB

Summary: Nivolumab + Ipilimumab and Nivolumab + Chemotherapy in 1L NSCLC With <1% Tumor PD-L1 Expression Presented By Hossein Borghaei at 2018 ASCO Annual Meeting

Second Line Options for Squamous Cell Carcinoma of the Lung 62

REVEL: Study Design Presented By Maurice Perol at 2014 ASCO Annual Meeting

Overall Survival ITT Population Presented By Maurice Perol at 2014 ASCO Annual Meeting

OS for Nivolumab vs. Docetaxel as second line option in squamous Cell carcinoma, Checkmate 017.

Atezolizumab: Overall survival, ITT (n = 850) and PD-L1 subgroups Overall Survival (%) Atezolizumab Docetaxel HR, 0.73 a (95% CI, 0.62, 0.87) P = 0.0003 Minimum follow up = 19 months OS HR Subgroup 0.41 TC3 or IC3 TC2/3 or IC2/3 TC1/2/3 or IC1/2/3 a TC0 and IC0 0.67 0.74 0.75 Median OS, mo Atezolizumab Docetaxel n = 425 n = 425 20.5 8.9 16.3 10.8 15.7 10.3 12.6 8.9 Median 9.6 mo (95% CI, 8.6, 11.2) Median 13.8 mo (95% CI, 11.8, 15.7) ITT a 0.73 13.8 9.6 Months No. at risk Atezolizumab 425 363 305 248 218 188 157 74 28 1 Docetaxel 425 336 263 195 151 123 98 51 16 0 0.2 1 2 In favor of atezolizumab Hazard Ratio a In favor of docetaxel a Stratified HR for ITT and TC1/2/3 or IC1/2/3. Unstratified HR for other subgroups. TC, tumor cells; IC, tumor-infiltrating immune cells; OS, overall survival. Barlesi et al. ESMO 2016 LBA44 Gadgeel et al., WCLC 2016

Atezolizumab Survival Benefit by Histology Compared to Docetaxel OS results from OAK: a randomized Phase III clinical trial: 2 Gadgeel et al., WCLC 2016

Afatinib vs. Erlotinib as second line options for Squamous Cell carcinoma of the lung

LUNG-MAP Schema Matched Sub-studies Non-match Sub-studies PI3K CDK4/6 FGFR 1 HRD Checkpoint Naive Checkpoint Refractory Stage 1 Stage 2 GDC-0032 Palbociclib AZD4547 BMN 673* Nivo/Ipi vs Nivolumab MEDI4736/ Treme* Vs SOC GDC-0032 Vs SoC Palbociclib Vs Soc AZD4547 Vs SoC BMN 673 Vs SoC* Lung-MAP amended to 2 nd line therapy & beyond to accommodate Nivolumab approval Pre-screening added back Eligibility criteria broadened; *Sub-studies in development Gadgeel et al., WCLC 2016

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